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CPR Exam 2 > 5. Erythrocyte and Heme Biochem > Flashcards

5. Erythrocyte and Heme Biochem Flashcards

1
Q

what is the average lifespan of RBCs

A

120 days

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2
Q

what is the structure of fetal Hb

A

Hb F = alpha2-gamma2

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3
Q

what are the components of adult Hb & which presents in higher quantity

A

Hb A = alpha2-beta2 = 97%

or alpha2-delta2

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4
Q

why does gamma levels drop and beta levels rise after birth

A

switching from Hb F to Hb A

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5
Q

what is the function of heme

and how is it incorporated in Hb

A

has Fe2+ & help carry O2

hydrophobic compound - 1 per subunit

total 4 hemes in Hb

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6
Q

what happens to confirmation of heme as O2 binds

A

usually Fe2+ slightly outside of plane

once O2 binds - Fe2+ moves into plane –> pulls down proximal histidine of Hb and changes interaction w/ associated globin chains

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7
Q

what it the difference btn the O2 dissociation curves of myglobin vs hemoglobin

A

myoglobin = hyperbolic

hemoglobin = sigmoidal - bc of cooperativity - as one O2 binds, makes O2 binding easier in other globin subunits

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8
Q

what is positive cooperativity

A

Hb binds O2 in cooperative manner

-one heme subunit binds O2 and facilitates binding of O2 in other heme subunit b/c confirmaiton change

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9
Q

At which stage of RBC development is the majority of Hb developed?

A

before extrusion of nucleus from normoblast

small amount is made in reticulocyte

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10
Q

How does a decreased pH and/or high 2,3-BPG affect affinity of O2 for Hb?

what is the purpose of this

A

decreases affinity

favor the release of O2 at level of tissues

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11
Q

what is the modulation that occurs with exercise

A

PO2 drops from 40 to 20 torr in exercising tissues

-favoring release of O2 to tissues

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12
Q

Why does fetal hemoglobin have a higher affinity for O2 than adult hemoglobin?

A

HbF = 2 alpha and 2 gamma chains

–> binds poorly to 2,3-BPG, –> increasing affinity for O2

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13
Q

what is the mutation that occurs in sickle cell anemia

& what is the consequence

A

glutamic acid –> valine at AA #6 in beta-globin

case polymerization, sickle shape RBCs - impede circulation

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14
Q

What is the current treatment for sickle cell anemia?

A

hydroxyurea to induce HbF

BUT its also an antineoplastic agent -toxic chemotherapeutic agent

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15
Q

where is iron most located in humans & where is it stored

A

Hb = 67% (vs, myoglobin- 5% and proteins- 1%)

stored = 27% - in intestines, liver, spleen & bone marrow

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16
Q

What does iron play a role in?

A

O2 transport in Hb and myoglobin

& ETC as a component of cytochromes

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17
Q

how is iron regulated

A

modulation of absorption

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18
Q

what happens to Fe2+ (animal product) after ingestion

A

enter enterocyte –> oxidize to Fe3+ by Ferrosxidase

–> store in ferritin –> can degrade and store in hemosiderin

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19
Q

what happens to non heme iron (Fe3+) from plant products after its ingested

A

convert to Fe2+ by ferric reductase (Dcytb) w/ the help of Vit C

  • now its easily abs and enters enterocyte via divalent transporter-1 (DMT1)
  • converted to Fe3+ by ferroxidase for storage OR export out of enterocyte by ferroportin
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20
Q

what is ferroportin

A

helps export Fe2+ out of enterocyte

needs Hephaestin for fxn

regulated by Hepcidin

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21
Q

what happesn once Fe2+ is in the blood

A

its converted to Fe3+ by ferroxidase

Fe3+ then binds transferrin for transport to target tissues

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22
Q

how does the uptake of transferrin happen?

A

receptor mediated endocytosis via transferrin receptor (TfR)

  • internalized via clathrin into endosome
  • low pH of endosome - release transferrin from receptor
  • uptake iron in mito via DMT1
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23
Q

how is iron homeostasis regulated

A

modulate abs by Hepcidin (made in liver)

bind to ferroportin when high Fe levels - internalize ferroportin and degrades in lysosome –> decrase iron abs

aka kills the transporter

*hepcidin is regulated by protein transferrin, its receptor and human homeostatic iron regulator protein (HFE)

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24
Q

what are causes of iron deficiency

and what does it lead to

A

insufficient dietary iron/abs, excess blood loss, overuse of asprin, ulcer of GI tract

causes hypochromic microcytic anemia

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25
Q

what is hereditary hemochromatosis (HH)

how does it happen, what does it lead to and how do you treat it

A

increased abs of iron –> accumulate in heart, liver and pancreas

==> lead to liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis & heart failure

= auto recessive - mutation in hereditary hemochromatosis gene - iron overlad = 15 g in body (instead of 3)

treat w/ blood letting nad iron chelators

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26
Q

what do you get if you have a deficiency of folate & vit B12

A

megaloblastic anemia –> large RBCs - MCV > 100 fL but normal Hb content in relation to size

-occurs bc diminished synthesis of DNA in RBC development

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27
Q

how does megaloblastic macrocytic anemic look in bone marrow vs RBCs

A

bone marrow: large RBCs & hypersegmented neutrophils

RBCs- increased vol & macrocytic, normochromic cells in blood smear

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28
Q

what reduces folate & what does it make

A

dihydrofolate reductace

1st add 2 H+ - DHF and then add 2 more = THF= active from

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29
Q

why is THF important

A

synthesis of purines and pyrimidine thymine

-vital role in DNA synthesis

-1 C transfer - gene regulation and synthetic path for choline, serine, glycine and methionine

30
Q

how is folic acid abs-ed

A

abs in SI (jejunum)

most dietary = DHF so after abs reduce to N5-methyl-THF - primary circulating form

liver stores 5-10 mg folate (last up 3-6 months)

31
Q

what is methotrexate and how does it work

A

antineoplastic agent

inhibitor of DNA synthesis (inhibit dihydrofolate reductase –> dont reduce DHF to THF ==> so no DNA & purine synthesis)

32
Q

what happens if you dont have Vit B12

A

folate trap

folate stuck as N5-methyl-THF

so cant remove methyl group to get THF –> mess with purine, pyr & DNA synthesis

33
Q

how does most of B12 deficiency occur

A

lack of intrinsic factor

  • supposed to carry B12 to ileum from where its released to blood stream
  • w/o it you have trouble abs-ing B12
34
Q

How is dietary B12 absorbed?

A
    • R-binder proteins bind B12 in stomach
    • Intrinsic factor made by parietal cells
    • pancreas produces proteases to release B12 from R-binder proteins
    • Intrinsic factor carries B12 do ileum where it is absorbed
    • IF-B12 complex is carried by transcobalamin II
  6. IF-B12 complex taken up by cells via receptor mediated endocytosis
35
Q

what is pernicious anemia

A

Vit B12 deficiency bc lack of intrinsic factor

a type of megaloblastic macrocytic anemia

36
Q

What is considered a low serum folate?

A

<3 ng/mL

37
Q

What is considered a low serum B12?

A

<350 pg/mL

38
Q

What is the Schilling test?

A

a test that measures vitamin B12 absorption with and without intrinsic factor;

if radioactive B12 present when administering CO-labeled B12 w/ IF then pos for pernicious anemia

test for pernicious anemia

39
Q

what is the structure of heme

A

heterocyclic perphyrin ring w/ iron present in center

four 5-membered rings w/ N connected by single C

-Fe2+

40
Q

what are the 3 phases of heme biosynthesis & where do they occur

A
  1. mitochondrial
  2. cytosolic
  3. mitochondial

primarily in liver and erythroid cells of bone marrow

41
Q

what are the steps of the 1st phase of heme synthesis

A

purpose = generate ALA

42
Q

what are the steps of phase 2 of heme biosynthesis

A

purpose = generate coproporphyrinogen III (has porphyrin rings)

43
Q

what is the 3rd phase of heme synthesis

A

purpose = generation of protoporphyrin & intoduction of iron to from heme

44
Q

what does ALA synthase need to work

A

needs B6

-w/o B6- anemia bc heme synthesis doesnt occur

45
Q

what happens in lead poisoning

A

lead inactivates ALA dehydratase & Ferrochelatase

get accumulation of:

  1. ALA - neurotoxic - lead to neurological symptoms
  2. protoporphyrin IX

cause anemia (microcytic & hypochromic) & impacts ATP synthesis & energy metabolism

46
Q

what are porphyrias & how are they caused

A

inherited metabolic disorder

-defects in heme systhesis

types depend on where synthesis is inhibited

47
Q

what is acute intermittent porphyria caused by

& what are its consequences

A

defective PBG deaminase in liver

= auto dom

-excess production of ALA & PBG

periodic attach of abdominal pain & neurolocial dysfxn

type = hepatic porphyria

48
Q

what is congenital erythropoietic porphyria & what are is its consequences

A

defective uropophyrinogen III synthase (in RBCs)

= auto rec

-accumulate uroporphyrinogen I and its red colored, oxidation product uroporphrin I

==> photosensitivity, red urine and teeth, hemolytic anemia

type = erythropoietic porphyria

49
Q

what is the cause for porphyria cutanea tarda & what are its consequences

A

defective uroporphyrinogen decarboxylase

  • auto dom
  • accumulate uroporphyinogen III –> converts to urophorphyinogen I and uroporphyrin oxidation products

==> photosensitivity, results in vesicles and bullae on skin, wine red urine

type = hematoerythropoietic

50
Q

what is the cause of variegate porphryia & what does it lead to

A

defective protoporphyrinogen IX oxidase

-auto dom (aka celebrity porphyrias)

==> photosensitivity and neurologic symptoms and development delay in children, intermittent episodes of abd pain, delirum, hallucinations/convulsions

type = hepatic porphyria

51
Q

what is the reticulo-endothelial system

A

system that degrades Hb into globin and heme

globin broken down to AA and heme is processed fro degradation

52
Q

what is heme oxygenase and what is the result of its rxn

A

enzyme that removes bridge btn pyrrole rings of heme (require O2)

relase CO, oxidize iron to ferric form, make biliverdin

53
Q

what converts biliverdin to bilirubin

A

biliverdin reductase

54
Q

What is free bilirubin bound to and where is it transported to?

A

albumin -> transported to liver where it is conjugated

55
Q

What is the rate limiting enzyme in bilirubin conjugation?

A

UDP glucuronyl transferase

rxn = BR-monoglucuronide –> BR-diglucuronide f

56
Q

What is the fate of conjugated bilirubin (bilirubin-diglucuronide)?

A

empty into the gall bladder

57
Q

What are the products of BR-diglucuronide when released from the gall bladder into the small intestine? *(released in response to food)

A
  1. reduction to urobilinogen
  2. some urobilinogen is reabsorbed by kidneys to make urobilin (yellow pigment in urine)
  3. stercobilin (red-brown pigment in feces)
58
Q

What are normal levels of unconjugated and conjugated bilirubin?

A

unconjugated: 0.2-0.9 mg/dL
conjugated: 0.1-0.3 mg/dL

59
Q

What is the cause of pre-hepatic jaundice?

A

Increased unconjugated bilirubin production

(hemolytic anemias may cause this)

ex: excess hemolysis, internal hemorrhage, incompatibility of maternal-fetal blood group, uptake capacity of liver uptake

60
Q

What are the clinical findings in pre-hepatic jaundice?

A

elevated unconjugated levels of BR

normal ALT and AST (bc everything beyond the liver is fine)

urobilinogen in urine

61
Q

What is the cause of intra-hepatic jaundice?

A
  • impaired hepatic uptake, conjugation, or secretion of conjugated BR
  • Can be caused by cirrhosis, hepatitis, Criggler-Najjar syndrome, and Gilbert syndrome
62
Q

What are the clinical findings of intra-hepatic jaundice?

A

increase in ALT and AST

variable increase in unconjugated/conjugated BR

normal urobilinogen levels in urine

63
Q

What are the causes of post-hepatic jaundice?

A

Defect with bilirubin excretion/decreased bile flow

caused by obstruction to biliary drainage, cholangiocarcinoma, gallstones, lesions, drugs

64
Q

What are the clinical findings in post-hepatic jaundice?

A
  1. elevated blood levels of conjugated BR
  2. Normal AST and ALT
  3. Conjugated BR in urine (dark)
  4. No urobilinogen in urine
  5. No stercobilin in feces (pale stool)
65
Q

What is the cause of neonatal jaundice?

A

Immature hepatic metabolic pathways

deficiency of UDP-GT enzyme

breakdown of fetal Hb as it is replaced with adult Hb –> accumulate excess BR

66
Q

What is the treatment for neonatal jaundice?

A
  1. phototherapy (blue fluorescent light causes BR to convert to more soluble isomer)
  2. IM injection of tin-mesoporphyrin (inhibits heme oxygenase)
67
Q

What is the cause of Type 1 Criggler-Najjar syndrome?

A

UDP-GT deficiency: complete absence of gene

=severe hyperbilirubinemia

BR accumulates in brain –> cause kernicturus (encephalopathy)

68
Q

What is the treatment of Type 1 Criggler-Najjar syndrome?

A

blood transfusions

phototherapy

heme oxygenase inhibitor

oral CaPO4 and carbonate

liver transplant

69
Q

What are the two benign UDP-GT disorders?

A

Type II Criggler-Najjar syndrome and Gilbert syndrome

70
Q

What is the color progression of a bruise and their associated hemoglobin byproduct?

A
  • Red = heme
  • green = biliverdin
  • orange = bilirubin
  • reddish brown = hemosiderin

CPR Exam 2 (20 decks)

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